Dithio derivatives of 4,5-dihydro-1H-pyrrole-2-carboxylic acids and 1,4,5,6-tetrahydropyridine-2-carboxylic acids

ABSTRACT

New mercaptoacyl derivatives of 4,5-dihydro-1H-pyrrole-2-carboxylic acids and 1,4,5,6-tetrahydropyridine-2-carboxylic acids having the general formula ##STR1## are useful as hypotensive agents.

This is a division of application Ser. No. 967,827, Dec. 8, 1978.

SUMMARY OF THE INVENTION

This invention relates to new mercaptoacyl derivatives of4,5-dihydro-1H-pyrrole-2-carboxylic acids and1,4,5,6-tetrahydropyridine-2-carboxylic acids (2,3-dehydropipecolicacids) which have the formula (I) ##STR2## wherein R is hydrogen orlower alkyl;

R₁ is hydrogen, hydroxy, halogen or lower alkoxy;

R₂ is hydrogen or lower alkyl;

R₃ is hydrogen, lower alkanoyl or ##STR3## m and n each is 0 or 1; andto salts thereof.

The asterisks indicate centers of asymmetry. The carbon atom isasymmetric when R₁ or R₂ are other than hydrogen.

BACKGROUND OF THE INVENTION

In copending application Ser. No. 878,144, filed Feb. 15, 1978, byMiguel Angel Ondetti and Sesha Iyer Natarajan, now U.S. Pat. No.4,129,566 there are described derivatives of 3,4-dehydroproline and4,5-dehydropipecolic acid which have the formula ##STR4## wherein R andR₂ each is hydrogen or lower alkyl;

R₁ is hydrogen, lower alkanoyl or ##STR5## m and n each is 0 or 1, andto salts thereof.

These compounds, it will be observed, have a double bond between thesecond and third carbons from the nitrogen in a clockwise direction,carbons not attached to the carboxy group. These compounds are obtainedfrom starting materials with the formula ##STR6##

The compounds of this invention are distinguishable by a double bondjoining the carbon bearing the carboxy group and its adjacent carbon,carbons more distant from the nitrogen in a clockwise direction. Suchcompounds are not obtainable by the methods described in the priorapplication. We have found that the compounds of this invention can beobtained by a different route described below and furthermore similar R₁-substituted compounds of this description can be obtained whereas onlyring unsubstituted compound of the prior type are available.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to mercaptoacyl derivatives of4,5-dihydro-1H-pyrrole-2-carboxylic acids and1,4,5,6-tetrahydropyridine-2-carboxylic acids, and salts thereof, whichhave formula I above.

Within the class described, there are especially preferred thosecompounds of formula I wherein R is hydrogen or lower alkyl, especiallyhydrogen or t-butyl; R₁ is hydrogen, hydroxy or halogen, especiallyhydrogen; R₂ is hydrogen or lower alkyl, especially hydrogen or methyl;R₃ is hydrogen or lower alkanoyl, especially hydrogen or acetyl; m is 0and n is 1.

The lower alkyl groups represented by the symbols are straight orbranched chain hydrocarbon radicals having up to 7 carbon atoms, e.g.,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl and the like.The lower alkoxy groups are of the same type, e.g., methoxy, ethoxy,propoxy, isobutoxy, etc. The C₁ -C₄ members, especially C₁ and C₂members, are preferred.

The lower alkanoyl groups are those having the acyl radicals of thelower fatty acids, i.e., those having up to 7 carbon atoms, for example,acetyl, propionyl, butyryl, isobutyryl, etc. Similarly, the loweralkanoyl groups having up to 4 carbons, and especially acetyl, arepreferred.

The halogens are the four common halogens, fluorine being preferred.

The compounds of formula I are produced by the addition of an acidchloride having the formula ##STR7## wherein R₃ is lower alkanoyl and Xis halogen, preferably chlorine,

to the dehydroimino acid ester having the formula ##STR8## wherein R islower alkyl, in an inert organic solvent like dichloromethane,chloroform, benzene, toluene or the like at a reduced temperature, e.g.,in the range of about -5° to +5° C., to give the intermediate having theformula ##STR9##

The intermediate of formula IV, which need not be isolated isdehalogenated, e.g., with a strong base such as1,5-diazabicyclo-[5.4.0]undec-5-ene in an inert organic solvent likedichloromethane, chloroform, benzene, toluene at a reduced temperature,e.g., in the range of about -5° to +5° C. to give a compound of formulaI wherein R is lower alkyl and R₃ is lower alkanoyl.

To obtain the compound of formula I wherein R is hydrogen, the ester canbe treated with trifluoroacetic acid and anisole when R is the preferredt-butyl.

Treatment with a base like aqueous ammonia or sodium hydroxide removesthe R₃ lower alkanoyl group.

To obtain the bis compound or "dimer" of formula I, i.e., wherein R₃ isthe radical ##STR10## the corresponding compound wherein R₃ is hydrogenis directly oxidized, e.g., with alcoholic iodine solution.Alternatively the dehydro imino acid ester of formula III is acylatedwith dithio dialkanoyl chloride having the formula ##STR11## wherein Xis halogen, preferably chlorine, and R₂ and n have the same meaning asabove.

The starting materials of formula III are obtained by N-chlorination ofthe amino acid ester with tert.-butyl hypochlorite followed bydehydrohalogenation with a strong base, e.g., sodium or potassiumalkoxides.

The products of formula I have centers of asymmetry indicated by theasterisk in formula I. The compounds accordingly exist in stereoisomericforms or in racemic mixtures thereof. All of these are within the scopeof the invention. The starting material can be in the form of one of theenantiomers or racemic mixtures thereof. When the product is in the formof a racemate, the stereoisomers can be separated by conventionalchromatographic or fractional crystallization methods.

Alternatively the optically active form of the acyl side chain, thedehydro imino acid ester or both can be used in the synthetic proceduresto obtain the stereoisomeric form desired.

The compounds of this invention from basic salts with various inorganicand organic bases which are also within the scope of the invention. Suchsalts include ammonium salts, alkali metal salts like sodium andpotassium salts (which are preferred), alkaline earth metal salts likethe calcium and magnesium salts, salts with organic bases, e.g.,dicyclohexylamine salt, benzathine, N-methyl-D-glucamine, hydrabamine,salts with amino acids like arginine, lysine and the like. Thenon-toxic, physiologically acceptable salts are preferred, althoughother salts are also useful, e.g., in isolating or purifying theproduct.

The salts are formed in conventional manner by reacting the free acidform of the product with one or more equivalents of the appropriate baseproviding the desired cation in a solvent or medium in which the salt isinsoluble, or in water and removing the water by freeze drying. Byneutralizing the salt with an insoluble acid like a cation exchangeresin in the hydrogen form (e.g., polystyrene sulfonic acid resin likeDowex 50) or with an aqueous acid, and extraction with an organicsolvent, e.g., ethyl acetate, dichloromethane or the like, the free acidform can be obtained, and, if desired, another salt formed.

Additional experimental details are found in the examples which arepreferred embodiments and also serve as models for the preparation ofother members of the group.

The compounds of this invention are useful as hypotensive agents. Theyinhibit the conversion of the decapeptide angiotensin I to angiotensinII by angiotensin converting enzyme and therefore are useful in reducingor relieving angiotensin related hypertension. Thus by theadministration of a composition containing one or a combination ofcompounds of formula I or physiologically acceptable salt thereof,angiotensin dependent hypertension in the species of mammal sufferingtherefrom, e.g., in mice, rats, dogs, cats, etc., is alleviated orreduced. A single dose, or preferably two to four divided daily doses,provided on a basis of about 0.1 to 100 mg. per kilogram per day,preferably about 1 to 50 mg. per kilogram per day is appropriate toreduce blood pressure as indicated in the animal model experimentsdescribed by S. L. Engel, T. R. Schaeffer, M. H. Waugh and B. Rubin,Proc. Soc. Exp. Biol. Med. 143, 483 (1973). The substance is preferablyadministered orally, but parenteral routes such as subcutaneously,intramuscularly, intravenously or intraperitoneally can also beemployed.

The compounds of this invention can be utilized to achieve the reductionof blood pressure by formulating in compositions such as tablets,capsules or elixirs for oral administration (which is preferred) or insterile solutions or suspensions for parenteral administration. About 10to 500 mg. of a compound or mixture of compounds of formula I orphysiologically acceptable salt is compounded with a physiologicallyacceptable vehicle, carrier, excipient, binder, preservative,stabilizer, flavor, etc., in a unit dosage form as called for byaccepted pharmaceutical practice. The amount of active substance inthese compositions or preparations is such that a suitable dosage in therange indicated is obtained.

The following examples are illustrative of the invention and constitutepreferred embodiments. All temperatures are in degrees Celsius.

EXAMPLE 1(±)-1-[3-(Acetylthio)-2-methyl-1-oxopropyl]-4,5-dihydro-1H-pyrrole-2-carboxylicacid (a) 1,2-Dehydroproline, t-butyl ester

To a stirred solution of 34.2 g. (0.20 mole) of proline t-butyl ester in600 ml. of ether at -5° to 0° is added dropwise over ten minutes 21.7 g.(23.9 ml.=0.20 mole) of freshly prepared t-butyl hypochlorite [Org.Syn., Coll. Vol. V, 184 (1973)]. During the addition, the temperature ismaintained at -5° to 0°. After the addition is complete, the solution isstirred at this temperature for an additional five minutes.

To the vigorously stirred solution is added rapidly (˜3-5 min.) asolution of 7.8 g. (0.20 mole) of potassium in freshly distilled dry(CaH₂) t-butanol. After the addition, the temperature of the reactionmixture is about 18°. The reaction vessel is removed from the coolingbath and stirred for thirty minutes. The reaction mixture is filteredthrough Celite (diatomaceous earth) and the filtrate concentrated invacuo. The residue is taken up in ether and washed with several portionsof water. The ether solution is dried and concentrated in vacuo to 36.1g. of yellow liquid. A trace of hydroquinone is added and the crudeproduct distilled, affording 22.4 g. of 1,2-dehydroproline, t-butylester (66%), b.p. 60°-62°/0.1 mm.

(b)(±)-1-[3-(Acetylthio)-2-methyl-1-oxopropyl]-4,5-dihydro-1H-pyrrole-2-carboxylicacid, t-butyl ester

To a stirred solution of 16.9 g. (0.10 mole) of freshly distilled1,2-dehydroproline t-butyl ester in 60 ml. of dichloromethane at -5° to0° is added dropwise over ten minutes, a solution of 18.1 g. (0.1 mole)of 3-acetylthio-2-methylpropanoyl chloride in 60 ml. of dichloromethane.During the addition the temperature is maintained at -5° to 0°, andafter the addition is complete the solution is stirred for five minutes.

To this stirred solution at -5° to 0° is added dropwise over ten minutesa solution of 15.2 g. (0.10 mole) of 1,5-diazabicyclo[5.4.0]undec-5-enein 60 ml. of dichloromethane. After the addition is complete, the cooledbath is removed, and the reaction mixture is stirred for one hour.

The yellow solution is washed with cold dilute hydrochloric acid,saturated aqueous sodium bicarbonate, dried, and concentrated in vacuoto 27.7 g. of oil. The oil is taken up in diisopropyl ether and chilled,affording 9.3 g. (30%) of crystalline solid(±)-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-4,5-dihydro-1H-pyrrole-2-carboxylicacid, t-butyl ester, m.p. 77°-80°.

(c)(±)-1-[3-(Acetylthio)-2-methyl-1-oxopropyl]-4,5-dihydro-1H-pyrrole-2-carboxylicacid

To a stirred solution of 6.26 g. (20 mmoles) of the ester from part b in22 ml. (21.6 g. =200 mmoles) of distilled anisole at 0°-5° is added 100ml. of distilled trifluoroacetic acid (precooled to 0°-5°). Theresulting solution is stirred at 0°-5° for one hour.

The trifluoroacetic acid is removed in vacuo, the residue is taken up inether, and this is thoroughly extracted with saturated aqueous sodiumbicarbonate. The combined extracts are back-washed with ether, acidifiedwith 10% aqueous potassium hydrogen sulfate, and this is thoroughlyextracted with ethyl acetate. The combined extracts are dried andconcentrated in vacuo to an oil which crystallizes on standing.Trituration of this solid with diisopropyl ether affords 4.45 g. (45%)of crystalline solid(±)-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-4,5-dihydro-1H-pyrrole-2-carboxylicacid. Recrystallization of a 1.5 g. sample from ethyl acetate-hexaneaffords an analytical sample (1.0 g.,) m.p. 83°-85°.

EXAMPLE 2(±)-4,5-Dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)1H-pyrrole-2-carboxylicacid

A mixture of 2.86 g. (11.2 mmoles) of(±)-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-4,5-dihydro-1H-pyrrole-2-carboxylicacid, 15 ml. of concentrated ammonium hydroxide, and 15 ml. of water isstirred at 0°-5° under argon for fifteen minutes (a clear solution isobtained within two minutes). The solution is acidified with cold dilutehydrochloric acid, and thoroughly extracted with ethyl acetate. Thecombined extracts are dried and concentrated in vacuo to a solid, whichgives 2.0 g. (83%) of crude(±)-4,5-dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-1H-pyrrole-2-carboxylicacid on trituration with ether. Recrystallization from ethyl acetateaffords an analytical sample (0.80 g.), m.p. 112°-114°.

EXAMPLE 3(±)-1-[3-(Acetylthio-2-methyl-1-oxopropyl]-4,5-dihydro-1H-pyrrole-2-carboxylicacid, methyl ester

By substituting 1,2-dehydroproline methyl ester [Chem. Ber., 108, 2547(1975)] in the procedure of Example 1b,(±)-1-[3-(acetylthio-2-methyl-1-oxopropyl]-4,5-dihydro-1H-pyrrole-2-carboxylicacid, methyl ester is obtained as a chromatographically pure oil afterchromatography on silica gel using 9:1 benzene-ethyl acetate as eluant.R_(f) =0.47 (silica gel, benzene:ethyl acetate, 1:1).

EXAMPLE 4 4,5-Dihydro-1-(2-acetylthio)-1H-pyrrole-2-carboxylic acidmethyl ester

By substituting 2-acetylthioacetyl chloride for the3-acetylthio2-methylpropanoyl chloride in the procedure of Example 3,4,5-dihydro-1-(2-acetylthio)-1H-pyrrole-2-carboxylic acid methyl esteris obtained.

EXAMPLE 5(±)-4,5-Dihydro-1-(2-mercapto-1-oxopropyl)-1H-pyrrole-2-carboxylic acid

By substituting 2-acetylthiopropanoyl chloride for the3-acetylthio-2-methylpropanoyl chloride in the procedure of Example 1and then submitting the product to the procedure of Example 2,(±)-4,5-dihydro-1-(2-mercapto-1-oxopropyl)-1H-pyrrole-2-carboxylic acidis obtained.

EXAMPLE 6

(±)-4,5-Dihydro-1-(2-ethyl-3-mercapto-1-oxopropyl)-1H-pyrrole-2-carboxylicacid

By substituting 3-acetylthio-2-ethylpropanoyl chloride for the3-acetylthio-2-methylpropanoyl chloride in the procedure of Example 1and then submitting the product to the procedure of Example 2,(±)-4,5-dihydro-1-(2-ethyl-3-mercapto-1-oxopropyl)-1H-pyrrole-2-carboxylicacid is obtained.

EXAMPLE 7

(±)-1-[3-(Butyrylthio)-2-methyl-1-oxopropyl]-4,5-dihydro-1H-pyrrole-2-carboxylicacid

By substituting 3-butyrylthio-2-methylpropanoyl chloride for the3-acetylthio-2-methylpropanoyl chloride in the procedure of Example 1,(±)-1-[3-(butyrylthio)-2-methyl-1-oxopropyl]-4,5-dihydro-1H-pyrrole-2-carboxylicacid is obtained.

EXAMPLE 8(±)-4,5-Dihydro-4-hydroxy-(3-mercapto-2-methyl-1-oxopropyl)-1H-pyrrole-2-carboxylicacid

By substituting 4-tert-butoxy-L-proline tert-butyl ester [prepared from4-tert-butoxy-L-hydroxy proline as described in J. Am. Chem. Soc., 82,3359 (1960) for L-proline] for the L-proline tert-butyl ester in theprocedure of Example 1 and then submitting the product to the procedureof Example 2,(±)-4,5-dihydro-4-hydroxy-(3-mercapto-2-methyl-1-oxopropyl)-1H-pyrrole-2-carboxylicacid is obtained.

EXAMPLE 91-(3-Acetylthio-1-oxopropyl)-4,5-dihydro-4-hydroxy-1H-pyrrole-2-carboxylicacid

By substituting 4-tert-butoxy-L-proline tert-butyl ester for theL-proline tert-butyl ester and 3-acetylthiopropanoyl chloride for the3-acethylthio-2-methylpropanoyl chloride in the procedure of Example 1,1-(3-acetylthio-1-oxopropyl)-4,5-dihydro-4-hydroxy-1H-pyrrole-2-carboxylicacid is obtained.

EXAMPLE 10(±)-4,5-Dihydro-4-hydroxy-1-(2-mercapto-1-oxopropyl)-1H-pyrrole-2-carboxylicacid

By susbtituting 4-tert-butoxy-L-proline tert-butyl ester for theL-proline tert-butyl ester in the procedure of Example 5,(±)-4,5-dihydro-4-hydroxy-1-(2-mercapto-1-oxopropyl)-1H-pyrrole-2-carboxylicacid is obtained.

EXAMPLE 11(±)-1-[3-(Acetylthio)-2-methyl-1-oxopropyl]-4,5-dihydro-4-fluoro-1H-pyrrole-2-carboxylicacid

By substituting 4-fluoroproline tert-butyl ester [prepared from4-fluoro-L-proline by the procedure described in J. Am. Chem. Soc., 82,3359 (1960) for L-proline] for the L-proline tert-butyl ester in theprocedure of Example 1,(±)-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-4,5-dihydro-4-fluoro-1H-pyrrole-2-carboxylicacid is obtained.

EXAMPLE 12(±)-4,5-Dihydro-4-fluoro-(3-mercapto-2-methyl-1-oxopropyl)-1H-pyrrole-2-carboxylicacid

By substituting(±)-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-4,5-dihydro-4-fluoro-1H-pyrrole-2-carboxylicacid for the(±)-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-4,5-dihydro-1H-pyrrole-2-carboxylicacid in the procedure of Example 2,(±)-4,5-dihydro-4-fluoro-(3-mercapto-2-methyl-1-oxopropyl)-1H-pyrrole-2-carboxylicacid is obtained.

EXAMPLE 134,5-Dihydro-4-chloro-1-(2-mercaptoacetyl)-1H-pyrrole-2-carboxylic acid

By substituting 4-chloro-L-proline tert-butyl ester [prepared from4-chloro-L-proline by the procedure described in J. Am. Chem. Soc., 82,3359 (1960) for L-proline] for the L-proline tert-butyl ester and2-acetylthioacetyl chloride for the 3-acetylthio-2-methylpropanoylchloride in the procedure of Example 1 and then submitting the productto the procedure of Example 2,4,5-dihydro-4-chloro-1-(2-mercaptoacetyl)-1H-pyrrole-2-carboxylic acidis obtained.

EXAMPLE 144,5-Dihydro-1-(3-mercapto-1-oxopropyl)-4-methoxy-1H-pyrrole-2-carboxylicacid

By substituting 4-methoxy-L-proline tert-butyl ester [prepared from4-methoxy-L-proline by the procedure described in J. Am. Chem. Soc., 82,3359 (1960) for L-proline] for the L-proline tert-butyl ester and3-acetylthiopropanoyl chloride for the 3-acetylthio-2-methylpropanoylchloride in the procedure of Example 1, and then submitting the productto the procedure of Example 2,4,5-dihydro-1-(3-mercapto-1-oxopropyl)-4-methoxy-1H-pyrrole-2-carboxylicacid is obtained.

EXAMPLE 15(±)-4,5-Dihydro-4-ethoxy-(2-mercapto-1-oxopropyl)-1H-pyrrole-2-carboxylicacid

By substituting 4-ethoxy-L-proline tert-butyl ester [prepared from4-ethoxy-L-proline by the procedure described in J. Am. Chem. Soc., 82,3359 (1960) for L-proline] for the L-proline tert-butyl ester andacetylthioacetyl chloride for the 3-acetylthio-2-methylpropanoylchloride in the procedure of Example 1, and then submitting the productto the procedure of Example 2,(±)-4,5-dihydro-4-ethoxy-(2-mercapto-1-oxopropyl)-1H-pyrrole-2-carboxylicacid is obtained.

EXAMPLE 16(±)-4,5-Dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-1H-pyrrole-2-carboxylicacid, sodium salt

A mixture of(±)-4,5-dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-1H-pyrrole-2-carboxylicacid and sodium bicarbonate in equimolar amounts is dissolved in water,and the solution is freeze-dried to give(±)-4,5-dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-1H-pyrrole-2-carboxylicacid, sodium salt.

EXAMPLE 171,1'-[Dithiobis-(±)-2-methyl-1-oxopropane-3,1-diyl)]-bis-4,5-dihydro-1H-pyrrole-2-carboxylicacid

To a solution of(±)-4,5-dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-1H-pyrrole-2-carboxylicacid, sodium salt, in water, a solution of iodine in ethanol is addeddropwise while maintaining the pH between 6 and 7 by careful addition ofdilute sodium hydroxide. When a yellow permanent color is obtained, afew drops of an aqueous solution of sodium thiosulfate is added and thepH is lowered to 2-3 by addition of concentrated hydrochloric acid. Theaqueous mixture is extracted with ethyl acetate and the organic phase isdried and concentrated to dryness in vacuo to give1,1'-[dithiobis-(±)-2-methyl-1-oxopropane-3,1-diyl)]bis-4,5-dihydro-1H-pyrrole-2-carboxylicacid.

EXAMPLE 184,5-Dihydro-1-(3-acetylthio)-1-oxopropyl)-4-methoxy-1H-pyrrole-2-carboxylicacid, methyl ester

By substituting 4-methoxy-L-proline methyl ester for the L-prolinemethyl ester in the procedure of Example 3,4,5-dihydro-1-(3-acetylthio-1-oxopropyl)-4-methoxy-1H-pyrrole-2-carboxylicacid, methyl ester is obtained.

EXAMPLE 19 2,3-Dehydro-1-(3-acetylthio-1-oxopropyl)pipecolic acid ethylester

By substituting L-pipecolic acid ethyl ester for the proline tert-butylester and 3-acetylthiopropanoyl chloride for the3-acetylthio-2-methylpropanoyl chloride in the procedure of Example 1,2,3-dehydro-1-(3-acetylthio-1-oxopropyl)pipecolic acid ethyl ester isobtained.

EXAMPLE 20 2,3-Dehydro-1-(3-mercapto-1-oxopropyl)pipecolic acid

By substituting L-pipecolic acid tert-butyl ester [prepared frompipecolic acid by the procedure described in J. Am. Chem. Soc., 82, 3359(1960) for L-proline] for the proline tert-butyl ester and3-acethylthiopropanoyl chloride for the 3-acetylthio-2-methyl propanoylchloride in the procedure of Example 1 and then submitting the productto the procedure of Example 2,2,3-dehydro-1-(3-mercapto-1-oxopropyl)pipecolic acid is obtained.

EXAMPLE 21 (±)-2,3-Dehydro-1-(3-mercapto-2-methyl-1-oxopropyl)pipecolicacid

By substituting pipecolic acid tert-butyl ester for the L-prolinetert-butyl ester in the procedure of Example 1, and then submitting theproduct to the procedure of Example 2,(±)-2,3-dehydro-1-(3-mercapto-2-methyl-1-oxopropyl)pipecolic acid isobtained.

EXAMPLE 22 (±)-2,3-Dehydro-1-(3-acetylthio-2-ethyl-1-oxopropyl)pipecolicacid

By substituting pipecolic acid tert-butyl ester for the L-prolinetert-butyl ester and 3-acetylthio-2-ethylpropanoyl chloride for the3-acetylthio-2-methylpropanoyl chloride in the procedure of Example 1,(±)-2,3-dehydro-1-(3-acetylthio-2-ethyl-1-oxopropyl)pipecolic acid isobtained.

EXAMPLE 23 (±)-2,3-Dehydro-1-(2-mercapto-1-oxopropyl)pipecolic acid

By substituting pipecolic acid tert-butyl ester for the L-prolinetert-butyl ester in the procedure of Example 5,(±)-2,3-dehydro-1-(2-mercapto-1-oxopropyl)pipecolic acid is obtained.

EXAMPLE 24 2,3-Dehydro-1-(3-butyrylthio-1-oxopropyl)pipecolic acid

By substituting pipecolic acid tert-butyl ester for the L-prolinetert-butyl ester and 3-butyrylthiopropanoyl chloride for the3-acetylthio-2-methylpropanoyl chloride in the procedure of Example 1,and then submitting the product to the procedure of Example 2,2,3-dehydro-1-(3-butyrylthio-1-oxypropyl)pipecolic acid is obtained.

EXAMPLE 25(±)-2,3-Dehydro-1-(2-acetylthio-1-oxopropyl)-5-hydroxypipecolic acid

By substituting 5-tert-butoxy-L-pipecolic acid tert-butyl ester[prepared from 5-hydroxy-L-pipecolic acid by the procedure described inJ.Am.Chem. Soc., 82, 3359 (1960) for L-proline] and2-acetylthiopropanoyl chloride for the 3-acetylthio-2-methylpropanoylchloride in the procedure of Example 1,(±)-2,3-dehydro-1-(2-acetylthio-1-oxopropyl)-5-hydroxypipecolic acid isobtained.

EXAMPLE 26 2,3-Dehydro-1-(2-mercaptoacetyl)-5-hydroxypipecolic acid

By substituting 5-tert-butoxy-L-pipecolic tert-butyl ester for theL-proline tert-butyl ester and acetylthioacetyl chloride for the3-mercapto-2-methylpropanoyl chloride in the procedure of Example 1, andthen submitting the product to the procedure of Example 2,2,3-dehydro-1-(2-mercaptoacetyl)-5-hydroxypipecolic acid is obtained.

EXAMPLE 27(±)-2,3-Dehydro-1-(3-mercapto-2-methyl-1-oxopropyl)-5-hydroxypipecolicacid

By substituting 5-tert-butoxy-L-pipecolic acid tert-butyl ester for theL-proline tert-butyl ester in the procedure of Example 1 and thensubmitting the product to the procedure of Example 2,(±)-2,3-dehydro-1-(3-mercapto-2-methyl-1-oxopropyl)-5-hydroxypipecolicacid is obtained.

EXAMPLE 282,3-Dehydro-5-fluoro-1-(3-mercapto-2-methyl-1-oxopropyl)pipecolic acid

By substituting 5-fluoropipecolic acid tert-butyl ester [prepared from5-hydroxypipecolic by the procedures described in Biochemistry, 4, 2507(1965) and in J. Am Chem. Soc., 82, 3359 (1960) for 4-fluoro-L-prolineand proline tert-butyl ester] for L-proline tert-butyl ester in theprocedure of Example 1 and then submitting the product to the procedureof Example 2,2,3-dehydro-5-fluoro-1-(3-mercapto-2-methyl-1-oxopropyl)pipecolic acidis obtained.

EXAMPLE 29 2,3-Dehydro-5-chloro-1-(2-mercaptoacetyl)pipecolic acid

By substituting 5-chloropipecolic acid tert-butyl ester [prepared from5-hydroxypipecolic acid by the procedures described in Aust. J. Chem.,20, 1493 (1967) and in J. Am. Chem. Soc., 82, 3359 (1960) for4-chloro-L-proline and L-proline tert-butyl ester] for L-prolinetert-butyl ester and 2-acetylthioacetyl chloride for the3-acetylthio-2-methylpropanoyl chloride in the procedure of Example 1,and then submitting the product to the procedure of Example 2,2,3-dehydro-5-chloro-1-(2-mercaptoacetyl)pipecolic acid is obtained.

EXAMPLE 30 2,3-Dehydro-1-(3-acetylthio-1-oxopropyl)-5-methoxypipecolicacid

By substituting 5-methoxypipecolic acid methyl ester [prepared from5-hydroxypipecolic acid by the procedure described in J. Chem. Soc. 429(1945) for 5-methoxyproline] for the L-proline methyl ester in theprocedure of Example 18,2,3-dehydro-1-(3-acetylthio-1-oxopropyl)-5-methoxypipecolic acid isobtained.

EXAMPLE 31 2,3-Dehydro-1-(3-mercapto-1-oxopropyl)-5-methoxypipecolicacid

By substituting 5-methoxypipecolic acid tert-butyl ester for the4-methoxy-L-proline tert-butyl ester in the procedure of Example 14,2,3-dehydro-1-(3-mercapto-1-oxopropyl)-5-methoxypipecolic acid isobtained.

EXAMPLE 32(±)-2,3-Dehydro-1-(3-mercapto-2-methyl-1-oxopropyl)-5-methoxypipecolicacid

By substituting 5-methoxypipecolic acid tert-butyl ester for theL-proline tert-butyl ester in the procedure of Example 1, and thensubmitting the product to the procedure of Example 2,(±)-2,3-dehydro-1-(3-mercapto-2-methyl-1-oxopropyl)-5-methoxypipecolicacid is obtained.

EXAMPLE 33 (±)-2,3-Dehydro-1-(3-mercapto-2-methyl-1-oxopropyl)pipecolicacid sodium salt

By substituting(±)-2,3-dehydro-1-(3-mercapto-2-methyl-1-oxopropyl)pipecolic acid forthe(±)-4,5-dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-1H-pyrrole-2-carboxylicacid in the procedure of Example 16,(±)-2,3-dehydro-1-(3-mercapto-2-methyl-1-oxopropyl)pipecolic acid sodiumsalt is obtained.

EXAMPLE 341,1'-[Dithiobis(2-methyl-1-oxopropane-3,1-diyl)]-bis-2,3-dehydropipecolicacid

By substituting(±)-2,3-dehydro-1-(3-mercapto-2-methyl-1-oxopropyl)pipecolic acid forthe(±)-4,5-dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-1H-pyrrole-2-carboxylicacid in the procedure of Example 17,1,1'-[dithiobis(2-methyl-1-oxopropane-3,1-diyl)]bis-2,3-dehydropipecolic acid is obtained.

EXAMPLE 35S-4,5-Dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-1H-pyrrole-2-carboxylicacid

By substituting S-3-acetylthio-2-methylpropanoyl chloride for the(±)-3-acetylthio-2-methylpropanoyl chloride in the procedure of Example1, and then submitting the product to the procedure of Example 2,S-4,5-dihydro-1-(3-mercapto-2-methyl-1-oxopropyl)-1H-pyrrole-2-carboxylicacid is obtained.

EXAMPLE 361-[3-Acetylthio-1-oxopropyl]-4,5-dihydro-1H-pyrrole-2-carboxylic acid,tert-butyl ester

By substituting 3-acetylthiopropanoyl chloride in the procedure ofExample 1b,1-[3-acetylthio-1-oxopropyl]-4,5-dihydro-1H-pyrrole-2-carboxylic acid,tert-butyl ester, m.p. 59°-62°, is obtained after recrystallization fromhexane.

EXAMPLE 371-[3-Acetylthio-1-oxopropyl]-4,5-dihydro-1H-pyrrole-2-carboxylic acid

By substituting1-[3-acetylthio-1-oxopropyl]-4,5-dihydro-1H-pyrrole-2-carboxylic acid,tert-butyl ester (Example 36) in the procedure of Example 1c,1-[3-acetylthio-1-oxopropyl]-4,5-dihydro-1H-pyrrole-2-carboxylic acid,m.p. 89°-91° (ethyl acetate) is obtained.

EXAMPLE 384,5-Dihydro-1-(3-mercapto-1-oxopropyl)-1H-pyrrole-2-carboxylic acid

By substituting1-[3-acetylthio-1-oxopropyl]-4,5-dihydro-1H-pyrrole-2-carboxylic acid(Example 37) in the procedure of Example 2,4,5-dihydro-1-(3-mercapto-1-oxopropyl)-1H-pyrrole-2-carboxylic acid,m.p. 94°-96° (ethyl acetate) is obtained.

EXAMPLE 391,1'-[Dithiobis-(1-oxo-3,1-propanediyl)]bis[4,5-dihydro-1H-pyrrole-2-carboxylicacid], tert-butyl ester

By substituting 3,3'-dithiodipropanoyl chloride in the procedure ofExample 1b,1,1'-[dithiobis-(1-oxo-3,1-propanediyl)]bis[4,5-dihydro-1H-pyrrole-2-carboxylicacid], tert-butyl ester is obtained as a chromatographically pure oilafter chromatography on silica gel using 4:1 benzene-ethyl acetate aseluant. R_(f) =0.50 (silica gel; benzene:ethyl acetate, 1:1).

EXAMPLE 401,1'-[Dithiobis(1-oxo-3,1-propanediyl)]bis[4,5-dihydro-1H-pyrrole-2-carboxylicacid]

By substituting1,1'-[dithiobis(1-oxo-3,1-propanediyl)]bis[4,5-dihydro-1H-pyrrole-2-carboxylicacid], tert-butyl ester (Example 39) in the procedure of Example 1c,1,1'-[dithiobis(1-oxo-3,1-propanediyl)]bis[4,5-dihydro-1H-pyrrole-2-carboxylicacid], m.p. 158°-160° (ethyl acetate-methanol) is obtained.

EXAMPLE 411,1'-[Dithiobis(1-oxo-3,1-propanediyl)]bis[4,5-dihydro-1H-pyrrole-2-carboxylicacid], methyl ester

By substituting both 1,2-dehydroproline methyl ester and3,3'-dithiodipropanoyl chloride in the procedure of Example 1b,1,1'-[dithiobis(1-oxo-3,1-propanediyl)]bis[4,5-dihydro-1H-pyrrole-2-carboxylicacid], methyl ester is obtained as a chromatographically pure oil afterchromatography on silica gel using 4:1 benzene-ethyl acetate as eluant.R_(f) =0.27 (silica gel; benzene:ethyl acetate, 1:1).

What is claimed is:
 1. A compound of the formula ##STR12## wherein R andR₂ each is hydrogen or lower alkyl;R₁ is hydrogen, hydroxy, halogen orlower alkoxy; R₃ ##STR13## m and n each is 0 or 1; and physiologicallyacceptable salts thereof.
 2. A compound as in claim 1 wherein m is
 0. 3.A compound as in claim 1 wherein m is
 1. 4. A compound as in claim 2wherein each R is methyl; each R₁ and R₂ is hydrogen; and n is
 1. 5. Acompound as in claim 2 wherein R, R₁ and R₂ each is hydrogen; and n is1.